Cardiovascular diseases are still the first cause of morbidity and mortality in the western world; among these, hypertension and heart failure are two of the most frequent diseases. Hypertension is one of the most important cardiovascular risk factors and more than one third of population over 60 suffer from this disease. Congestive heart failure affects 1-2% of the population and even 10% of the very elderly; the percentage is expected to rise (Sharpe N., et al, The Lancet, 1998, 352, (suppl. 1), 3-17). Beside, hypertension may be one of the most important causes of heart failure in the elderly (Eur. Heart J., 2001, 22, 1527-1560). Although a number of effective drugs are available for the treatment of both hypertension and heart failure, further research is in progress to find more effective and safe compounds. Several drugs are used in combination for the treatment of heart failure, and among positive inotropic agents, digoxin is the most prescribed digitalis cardiac glycoside that can improve the myocardial performance. A very well-known drawback of digitalis drugs is their arrhythmogenic side-effect. Evidence of digitalis toxicity emerges at two- to three-fold higher serum concentration than the therapeutic dose, such as disturbances of conduction and cardiac arrhythmias which are characteristics of digitalis toxicity (Hoffman, B. F.; Bigger, J. T, Digitalis and Allied Cardiac Glycosides. In The Pharmacological Basis of Therapeutics, 8th ed.; Goodman Gilman, A.; Nies, A. S.; Rail, T. W.; Taylor, P., Eds.; Pergamon Press, New York, 1990, pp 814-839).
The capability of the natural digitalis compounds to increase the myocardial force of contraction is strictly related to their cardenolide structure having a 17β-lactone on a 14-hydroxy-5β,14β-androstane skeleton.
In the field of 5α,14α-androstane derivatives some groups of compounds are reported to possess positive inotropic properties.
GB 1,175,219 and U.S. Pat. No. 3,580,905 disclose 3-(aminoalkoxycarbonylalkylene) steroid derivatives which possess digitalis-like activities with “a ratio between the dose which produces toxic symptoms (onset of cardiac arrhythmias) and the effective dose comparable with such a ratio as measured for standard cardiac glycosides”. Besides no clear advantage over digitalis glycosides, the compounds with the highest ratio produce the lowest increase in contractile force.
6-Hydroxy and 6-oxoandrostane derivatives are disclosed in EP 0 825 197 B1 as ligands and inhibitors of Na+,K+-ATPase, and positive inotropic agents possessing a lower toxicity when compared with digoxin, as evaluated on the basis of the acute toxicity in mice. The same compounds are also reported by S. De Munari, et al., J. Med. Chem. 2003, 46(17), 3644-3654.
The evidence that high levels of endogenous ouabain (EO), a closely related isomer of ouabain, are implicated in human hypertension and cardiac hypertrophy and failure stimulated the pharmacological research for developing novel anti-hypertensive agents active as ouabain antagonists. The pathogenetic mechanisms through which increased EO levels affect cardiovascular system involve the modulation of Na—K ATPase, the key enzyme responsible for renal tubular sodium reabsorption and the activation of signaling transduction pathways implicated in growth-related gene transcription. By studying both genetic and experimental rat models of hypertension and comparing them with humans, it has been demonstrated that elevated levels of circulating EO and the genetic polymorphism of the cytoskeletal protein adducin associate with hypertension and high renal Na—K pump activity. Ouabain itself induces hypertension and up-regulates renal Na—K pump when chronically infused at low doses into rats (OS). In renal cultured cells, either incubated for several days with nanomolar concentrations of ouabain or transfected with the hypertensive adducin genetic variant, the Na—K pump results enhanced. Moreover, both EO and adducin polymorphism affect cardiac complications associated to hypertension, the former through the activation of a signalling transduction pathway. As a consequence, a compound able to interact with the cellular and molecular alterations, sustained by EO or mutated adducin, may represent the suitable treatment for those patients in whom these mechanisms are at work (Ferrandi M et al., Curr Pharm Des. 2005; 11(25):3301-5).
As reported above, the crucial point of positive inotropic agents is the ability to discriminate between the potency in inducing an increase of myocardial force of contraction and the onset of cardiac arrhythmias.
There is still a constant need to make available drugs showing a better therapeutic ratio and/or a longer duration of action, both of them important factors for the compliance of patients. Preferably, such drugs should be suitable for oral administration.
Different steroids, with the B ring enlarged and/or with one carbon atom replaced by a heteroatom, are reported to possess different pharmacological activities as well as some action on the Na+,K+-ATPase or as diuretics.
3-Hydroxy and 3-keto B-homoandrostane derivatives are disclosed in JP 45023140, as anabolic and antiandrogenic steroids, and in U.S. Pat. No. 3,059,019 and by H. J. Ringold in J. Am. Chem. Soc., 1960, 82, 961-963, as anabolic and antigonadotrophic compounds.
Natural or synthetic brassinolides (2,3-dihydroxy-6-keto-7-oxa-7a-homo derivatives) are reported to be plant growth regulators (CS 274530) and some of them are inhibitors or stimulators of Na+,K+-ATPase (L. Starka, et al., Sbornik Lekarski, 1997, 98, 21-25).
6-Azaestranes are claimed in U.S. Pat. No. 3,328,408 as diuretic and hypoglycemic agents and hence useful in the treatment of congestive heart failure.
Compounds resembling steroidal structures with an oxygen atom in the B ring are reported by R. K. Razdan et al. in J. Med. Chem., 1976, 19, 719-721, as inactive or almost inactive agents in hypertensive rats, even though their dosage was quite high (10 mg/kg).